Esters of testosterone and 19-nortestosterone and method for the production thereof



ESTERS OF TESTOSTERONE AND 19-NORTESTOS- TERONE AND METHOD F OR THE PRODUCTION THEREOF Egon Richard Diczfalusy, Ronninge, and Ove Birger 1 Fernii, Hans Jakob Fex, and Knut Bertil Hiigberg, Halsingborg, Sweden, as'signors to Aktiebolaget Leo, Halsingborg, Sweden, a Swedish firm No Drawing. Application January 20, 1958 Serial No. 709,764

5 Claims. (Cl. 260-3914) The invention relates to new esters of testosterone and of 19-nortestosterone, and to the production of the said esters.

Androgens are generally administered by injections because the androgenic effect is usually'impaired on oral administration. By the injections, the androgenic compounds are preferably dissolved or suspended inoils, such as sesame-oil or other vegetable oils.

It is known that in some cases esterification of steroid hormones containing a hydroxyl group intensifies and prolongs the hormonal action. Thus for several years, testosterone has been administered as the propionate.

Even if considerably better therapeutic results were obtained by using testosterone propionate' instead of testosterone itself, the search for new esters with a still better eifect has been continued, cf. for instance Ott et al., Journal Clinical Endocrinology (Metabolism) 12: 15-27 (1952) and D. Gould et al., J. Am. Chem. Soc. 79: 4472-5 (1957), and has resulted in a series of new esters, the most effective of which seem .to be the 9- phenylpropionate, the enanthate, the hexahydrobenzoate and the {i-cyclopentylpropionate.

As a measure of the prolonged activity of an androgen is used the weight of the prostate or of the seminal vesicles in castrated animals after a single injection of the androgen. The following table I shows the activity of a number of known testosterone esters as determined on castrated rats. For each of the esters, the activity is given as the weight in milligram of the ventral lobe of the prostate (VL) and of the seminal vesicle (SV), respectively, 42 days after a single subcutaneous injection of the ester. The esters were given in equal volumes of peanut oil in every case and for each determination a group of 7 test animals were used so that each of the values given in the table represents'the averageof 7 weights.

TABLE I Dose in mg. 1 Testosterone ester of testos- VL in mg. SV in mg.

terone Proplonate Z fi-Phenylpropionate. Z "g:

2. 17 61 92 Enanthate i i 4. 35 106 134 Hexahydrobenzoate i fl-Oyclopentylpropionate Z:

The results show that the activity of the [3-phenylpropionate is only slightly better than that of the propionate,

ICC

2 sible for the organisms to utilize the anabolic or androgenic or anabolic and androgenic eiiects of the steroid in question to an increased degree.

It is a further object of the invention to provide new esters of testosterone and 19-nortestosterone which are able to maintain the said effect .or efiects in the organism for a longer period than are the non-esterified steroids or whereas the remaining esters show a substantial improvegroup of new esters of the androgens, testosterone and v 19-nortestosterone, the use of which esters makes it posthe known esters. Therby, the same or a better area: than hitherto obtainable can be obtained by reduced doses and a reduced number of injections. 1

The acid residues of the esters of the invention are -residues of ,B-(p-a1koxyphenyl) propionic acids of the wherein R represents an alkyl group of 1 to 12 carbon atoms, and the esters are produced according to the-invention by esterifying the steroid in question in the 17:- position with a derivative of an acid of the said kind suitable for the esterification.

In a preferred embodiment of the method of the-invention, an acid chloride or an anhydride of the acid in question is used, whereby the reaction generally proceeds smoothly and to satisfying yields at temperatures not exceeding room temperature.

a The lower members of the series of ,B-(p-alkoxyphenyD- propionic acids, having 1, 3 and 4 carbon atoms in the 'alkoxy group, the acid residues of which'may form part of the esters of the invention, are described in J. Am. Chem. Soc. 70, 255 (1948), and the corresponding acid chlorides are also described there. In Chemical Abstracts 49, '13 936i (1955) are described the fi-(p isopropoxyphenyl)-, fi-(p-isobutoxyphenyhand p-(p-isopentoxyphenyD-propionic acids.

Acids with other alkoxy groups can be produced either in a similar manner or from ,8-(p-hydroxyphenyl)-prqpionic acid or its esters, for example as described in}. Am. Chem. Soc. 68, 2598 (1946). For some of the acids, which were not hitherto describedin the literature, melting points given in the following table were found. Melting points for acids of the-formula 7 n M.P. 111 C.

The acid chlorides can be produced in known manner, for example by heating the corresponding acids with "a surplus of thionylchloride ona steam bath. ;The acid anhydrides can be produced in the manner described in J. Chem. Soc. 741 (1952).

The esterification according to the invention proceeds particularly smoothly in the presence of an organic base, such as pyridine, which may also serve as'a solvent during the esterificat'ion. However, also other solvents can be used, provided that they do not react with the acid derivative. Examples are chloroform, benzene, and" -e tlii er.

Table II below shows the activities of the known testosterone enanthate and of a number of esters of the invention as determined on castrated rats. Eacnof the activities given is the average of the weight of he ventral lobe of the prostate (VL) and of the se vesicle (SV), respectively, of 10" animals as deter 42 days after a single injection of the compoundto'b'e examples.

stands for 15 hours at room temperature.

. 3 tested. All injections were given subcutaneously and in equal volumes of isopropyl myristate.

. .The table shows that the activity of the esters of the invention is equal to or substantially exceeds that of the enanthate, particularly in the cases of the hexoxy compound. In a furtherlexperiment spayed rats were injected subcutaneously with testosterone enanthate and with hexoxy heptoxyand octoxyphenyl propionates of the invention in equal volumes of peanut oil. The results are given in Table III where each of the activities is given as the average of the weights of the ventral prostate lobe (VL) and of the seminal vesicle (SV), respectively, of 9 animals as determined 42 days after the injection.

TABLE III Testosterone ester Dose in mg. VL SV testosterone in mg. in mg.

T 4. 35 146 261 vEnanthate i 8.70 181 305 1 7 -Hexo hen 1 -pro onate.-- 3. 4

p Xyp y p 6. 8 677 1%0 fl-(p-Heptoxyphenyl)-propionate.. g -fi-(pOctoxyphenyD-proplonate.

.The table shows the particularly good results which are obtained when the alkoxy group in para-position of the phenyl group in the esters of the invention has 6, 7 'or. 8 carbon atoms, since substantially reduced doses of these new esters result in a higher androgenic activity 'than that obtained with higher doses of the known ester.

Finally the following Table IV gives the results of an experiment in which the weight determinations of the ventral prostate lobe (VL) and of the seminal vesicle (SV) of the test animals (castrated rats) were carried out 60 days after the injection. All injections were given subcutaneously in equal volumes of peanut oil. Each of the activities in Table IV is the average value of the weights of the organs from animals.

A comparison with the figures in table III shows that "the activity of the esters of the invention is more pro- :longed that than of the known ester.

The production of a number of testosterone esters according to the invention is illustrated by the following Example 1 To a solution of 3 g. of testosterone in ml. of dry pyridine, a solution of 4.2 g. of fi-(p-methoxyphenynpropionyl chloride in 15 ml.-of dry chloroform is added dropwise at a temperature about 0 C. with stirring. After the addition has been fininshed, the reaction mixture Then finely crushed ice is added in order to hydrolyse an excess of acid chloride. To the resulting mixture, a mixture of equal volumes of ether and ethyl acetate is added, and washing is carried out with dilute hydrochloric acid, water, sodium bicarbonate solution and water in the said order. The resulting ether-ethyl acetate phase is dried and evaporated to dryness. The residue is recrystallized from ethyl acetate. The resulting testosterone fl-(p-methoxyphenyl)-propionate melts at 145-l46 C. [a] =+83 (c=l in dioxane).

Example 2 To a solution of 1 g. of testosterone in 25 ml. of dry pyridine are added 2.4 g. of ,B-(p-methoxyphenyD-propionic acid anhydride (melting point 6062 C.), where after the reaction mixture stands for 15 hours at room temperature. After hydrolysis with ice, the working up proceeds as in Example 1. After the recrystallization from ethyl acetate, testosterone fl-(p-methoxyphenynpropionate with melting point 145-146 C. is obtained.

Example 3 Example 4 To a solution of 3 g. of testosterone in 15 ml. of dry pyridine, a solution of 5.6 g. of e-(p-hexoxyphenynpropionyl chloride is added dropwise at about 0 C. with stirring. After the addition, the reaction mixture stands for 15 hours at room temperature. The mixture is then hydrolysed with ice and worked up as in Example 1, whereby evaporation of the ether-ethyl acetate solution yields an oil which crystallizes from aqueous ethanol. The resulting testosterone fl-(p-hexoxyphenyl)-propionate melts at 59-60" C. [a] =+76 (0:1 in dioxane).

Example 5 To a solution of 1.5 g. of testosterone in a mixture of 10 ml. of dry chloroform and 5 ml. of dry pyridine, a solution of 3.9 g. of S-(p-dodecyloxyphenyl)-propionyl chloride in 10 ml. of dry chloroform is added dropwise at a temperature about 0 C. with stirring. After the addition, the reaction mixture is left for 15 hours at room temperature and is then hydrolysed with ice and worked up as in Example 1. By evaporation of the ether-ethyl acetate solution an oil is obtained which crystallizes from metha- The resulting testosterone S-(p-dodecyloxyphenybpropionate melts at 5859 C. [a] =+64 (0:1 in dioxane).

Example 6 To a solution of mg. of l9-nortestosterone in 5 ml. of dry pyridine are added 500 mg. of [i-(p-methoxyphenyl)-propionic acid anhydride, and the reaction mixture is left for 15 hours at room temperature. It is then hydrolysed with ice and worked up as in Example 1, whereby evaporation of the ether-ethyl acetate solution yields an oil which crystallizes from methanol. The resulting 19-nortestosterone fl-(p-methoxyphenyl)-propionate melts at 126-127 C. [a] +50 (c=1 in dioxane).

Example 7 To a solution of 5 g. of testosterone in 25 ml. of dry pyridine are added 10.9 'g. of[3-(p-hexoxyphenyD-propi- .onic acid anhydride (meltingpoint 47-48 C.), whereafter the reaction mixture stands for 15 hours at room temperature. After hydrolysis with ice, the working up is carried out as in Example 1, whereby, however, the product obtained by evaporation of the ether-ethyl acetate solution is recrystallized from aqueous methanol. The resulting testosterone B-(p-hexophenyl)-propionate is melting at 60-61" C.

Example 8 To a solution of 2 g. of testosterone in 25 ml. of dry pyridine are added 4.2 g. of fl-(p-isopropoxyphenyl)-propionic acid anhydride (isolated as an oil), whereafter the reaction mixture stands for 15 hours at room temperature. After hydrolysis with ice, the mixture is worked up as in Example 1, whereby evaporation of the etherethyl acetate solution yields an oil which is crystallized from aqueous methanol. The resulting testosterone B-(pisopropoxyphenyl)-propionate melts at 109-110 C. mn=+7s (c=1 in dioxane).

Example 9 To a solution of 1.5 g. of testosterone in 15 ml. of dry pyridine are added 3.5 g. of 8-(p-pentoxyphenyl)-propionic acid anhydride (melting point 45-46 C.), whereafter the reaction mixture stands for 15 hours at room temperature. After hydrolysis with ice, the working up is carried out as in Example 1, whereby the residue from the evaporation of the ether-ethyl acetate solution is crystallized from aqueous methanol. The resulting testosterone fi-(p-pentoxyphenyl)-propionate has the melting point 63-64 C. [u] =+76 (c=1 in dioxane).

Example 10 To a solution of 1.5 g. of testosterone in ml. of dry pyridine are added 4.0 g. of p-(p-heptoxyphenyl)-propionic acid anhydride (melting point 50-51 C.), whereafter the reaction mixture stands for 15 hours at room temperature. After hydrolysis with ice, the mixture is worked up as in Example 1, and the residue from evaporation of the ether-ethyl acetate solution is recrystallized from aqueous methanol, yielding testosterone fi-(p-heptoxyphenyD-propionate with melting point 57-58 C. [a] +69 (c=1 in dioxane).

Example 11 n-o-Qomomooon where R represents an alkyl group of not more than 12 carbon atoms.

2. 17-esters of testosterone and of 19-nortestosterone with fi-(p-alkoxypheny1)-propionic acids of the formula FOG-anathema wherein R represents an alkyl group of 6 to 8 carbon atoms.

3. The 17-ester of testosterone with p-(p-hexoxyphenyl)-propionic acid.

4. The 17-ester of testosterone with fi-(p-heptoxyphenyl) -propionic acid.

5. The 17-ester of testosterone with p-(p-octoxyphenyl)-propionic acid.

References Cited in the file of this patent UNITED STATES PATENTS 2,547,949 Lawson Apr. 10, 1951 2,683,725 Murray et a1 July 13, 1954 2,686,792 Murray et al Aug. 17, 1954 FOREIGN PATENTS 719,402 Great Britain Dec. 1, 1954 753,793 Great Britain Aug. 1, 1956 

1. 17-ESTERS OF TESTOSTERONE AND OF 19-NORTESTOSTERONE WITH B-(P-ALKOXYPHENYL)-PROPIONIC ACIDS OF THE FORMULA 